Hereditary spastic paraplegia

Gene: KIDINS220

Comment on mode of pathogenicity: Personal communication from Dmitrijs Rots (RadboudUMC). Prompted by the occurrence of a KIDINS220 nonsense variant in the middle of the gene, in a family without spastic paraplegia (HSP) or other features; an in-depth analysis of KIDINS220 variants was performed. It would appear that KIDINS220 gene is tolerant of LOF variants (nonsense, frameshift) in gnomAD population (hence pLI~ 0, in the PanelApp review by Dmitrijs Rots (RadboudUMC), 4 Nov 2021). This was unexpected, as KIDINS220-associated-HSP presents in childhood, so it would appear that haploinsufficiency is unlikely as the mechanism. In addition, there were nonsense/frameshift HSP-associated variants in KIDINS220, but they were located in the last two exons of the gene and so likely to escape nonsense mediated decay. Therefore, it is proposed that rather a LOF mechanism a dominant negative effect may be responsible, however, further cases need to be identified to confirm this.

Created: 18 Nov 2021, 4:11 p.m. | Last Modified: 18 Nov 2021, 4:11 p.m.

Panel Version: 1.272

Green List (high evidence)

Additional family reported in PMID: 33763417.
All reported pathogenic variants seems to locate in the last two exons, as well as pLI is ~0, so could be dominant negative ?

Created: 4 Nov 2021, 10:45 a.m. | Last Modified: 4 Nov 2021, 10:45 a.m.

Panel Version: 1.259

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spastic paraplegia; intellectual disability

Publications

• PMID: 33763417

Mode of pathogenicity
Other

Green List (high evidence)

Three unrelated cases presenting with ID, spasticity and other variable features.

Created: 2 Jan 2018, 3:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296